Intrazeolite assembly and pyrolysis of polyacrylonitrile

Radical polymerization of acrylonitrile within the pores of zeolites Y and mordenite produces intrazeolite polyacrylonitrile that can be pyrolysed to form conducting carbon filaments

CTEQ Parton Distributions and Flavor Dependence of Sea Quarks

This paper describes salient features of new sets of parton distributions obtained by the CTEQ Collaboration based on a comprehensive QCD global analysis of all available data. The accuracy of the new data on deep inelastic scattering structure functions obtained by the very high statistics NMC and CCFR experiments provides unprecedented sensitivity to the flavor dependence of the sea-quark distributions. In addition to much better determination of the small x dependence of all parton distributions, we found: (i) the strange quark distribution is much softer than the non-strange sea quarks and rises above the latter at small-x; and (ii) the difference $\bar d-\bar u$ changes sign as a function of x. A few alternative sets of viable distributions with conventional assumptions are also discussed.Comment: 13 pages with figures, MSUHEP-92-27, Fermilab-Pub-92/371, FSU-HEP-92-1225, ISU-NP-92-1

Accurate epigenetic aging in bottlenose dolphins (Tursiops truncatus), an essential step in the conservation of at-risk dolphins

Funding: This research was funded by SERDP grant RC20-C2-1097 awarded to Peter Tyack and Prescott Award NA20NMF4390132 awarded to Ashley Barratclough.Epigenetics, specifically DNA methylation, allows for the estimation of animal age from blood or remotely sampled skin. This multi-tissue epigenetic age estimation clock uses 110 longitudinal samples from 34 Navy bottlenose dolphins (Tursiops truncatus), identifying 195 cytosine-phosphate-guanine sites associated with chronological aging via cross-validation with one individual left out in each fold (R2 = 0.95). With a median absolute error of 2.5 years, this clock improves age estimation capacity in wild dolphins, helping conservation efforts and enabling a better understanding of population demographicsPublisher PDFPeer reviewe

Reversing age: Dual species measurement of epigenetic age with a single clock

Young blood plasma is known to confer beneficial effects on various organs in mice. However, it was not known whether young plasma rejuvenates cells and tissues at the epigenetic level; whether it alters the epigenetic clock, which is a highly-accurate molecular biomarker of aging. To address this question, we developed and validated six different epigenetic clocks for rat tissues that are based on DNA methylation values derived from n=593 tissue samples. As indicated by their respective names, the rat pan-tissue clock can be applied to DNA methylation profiles from all rat tissues, while the rat brain-, liver-, and blood clocks apply to the corresponding tissue types. We also developed two epigenetic clocks that apply to both human and rat tissues by adding n=850 human tissue samples to the training data. We employed these six clocks to investigate the rejuvenation effects of a plasma fraction treatment in different rat tissues. The treatment more than halved the epigenetic ages of blood, heart, and liver tissue. A less pronounced, but statistically significant, rejuvenation effect could be observed in the hypothalamus. The treatment was accompanied by progressive improvement in the function of these organs as ascertained through numerous biochemical/physiological biomarkers and behavioral responses to assess cognitive functions. Cellular senescence, which is not associated with epigenetic aging, was also considerably reduced in vital organs. Overall, this study demonstrates that a plasma-derived treatment markedly reverses aging according to epigenetic clocks and benchmark biomarkers of aging.Fil: Horvath, Steve. University of California at Los Angeles; Estados UnidosFil: Singh, Kavita. NMIMS University; IndiaFil: Raj, Ken. Public Health England; Reino UnidoFil: Khairnar, Shraddha. NMIMS University; IndiaFil: Sanghav, Akshay. Nugenics Research Pvt Ltd; IndiaFil: Shrivastava, Agnivesh. Nugenics Research Pvt Ltd; IndiaFil: Zoller, Joseph A.. University of California at Los Angeles; Estados UnidosFil: Li, Caesar Z.. University of California at Los Angeles; Estados UnidosFil: Hereñú, Claudia Beatriz. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Farmacología Experimental de Córdoba. Universidad Nacional de Córdoba. Facultad de Ciencias Químicas. Instituto de Farmacología Experimental de Córdoba; ArgentinaFil: Canatelli Mallat, Martina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Investigaciones Bioquímicas de La Plata "Prof. Dr. Rodolfo R. Brenner". Universidad Nacional de la Plata. Facultad de Ciencias Médicas. Instituto de Investigaciones Bioquímicas de La Plata "Prof. Dr. Rodolfo R. Brenner"; ArgentinaFil: Lehmann, Marianne. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Investigaciones Bioquímicas de La Plata "Prof. Dr. Rodolfo R. Brenner". Universidad Nacional de la Plata. Facultad de Ciencias Médicas. Instituto de Investigaciones Bioquímicas de La Plata "Prof. Dr. Rodolfo R. Brenner"; ArgentinaFil: Solberg Woods, Leah C.. Wake Forest University School of Medicine; Estados UnidosFil: Garcia Martinez, Angel. University of Tennessee; Estados UnidosFil: Wang, Tengfei. University of Tennessee; Estados UnidosFil: Chiavellini, Priscila. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Investigaciones Bioquímicas de La Plata "Prof. Dr. Rodolfo R. Brenner". Universidad Nacional de la Plata. Facultad de Ciencias Médicas. Instituto de Investigaciones Bioquímicas de La Plata "Prof. Dr. Rodolfo R. Brenner"; ArgentinaFil: Levine, Andrew J.. University of California at Los Angeles; Estados UnidosFil: Chen, Hao. University of Tennessee; Estados UnidosFil: Goya, Rodolfo Gustavo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Investigaciones Bioquímicas de La Plata "Prof. Dr. Rodolfo R. Brenner". Universidad Nacional de la Plata. Facultad de Ciencias Médicas. Instituto de Investigaciones Bioquímicas de La Plata "Prof. Dr. Rodolfo R. Brenner"; ArgentinaFil: Katcher, Harold L.. Nugenics Research Pvt Ltd; Indi

Plate-based diversity subset screening generation 2: An improved paradigm for high throughput screening of large compound files

High throughput screening (HTS) is an effective method for lead and probe discovery that is widely used in industry and academia to identify novel chemical matter and to initiate the drug discovery process. However, HTS can be time-consuming and costly and the use of subsets as an efficient alternative to screening these large collections has been investigated. Subsets may be selected on the basis of chemical diversity, molecular properties, biological activity diversity, or biological target focus. Previously we described a novel form of subset screening: plate-based diversity subset (PBDS) screening, in which the screening subset is constructed by plate selection (rather than individual compound cherry-picking), using algorithms that select for compound quality and chemical diversity on a plate basis. In this paper, we describe a second generation approach to the construction of an updated subset: PBDS2, using both plate and individual compound selection, that has an improved coverage of the chemical space of the screening file, whilst only selecting the same number of plates for screening. We describe the validation of PBDS2 and its successful use in hit and lead discovery. PBDS2 screening became the default mode of singleton (one compound per well) HTS for lead discovery in Pfizer

DNA methylation predicts age and provides insight into exceptional longevity of bats

This work was supported by a Paul G. Allen Frontiers Group grant to S.H., the University of Maryland, College of Computer, Mathematical and Natural Sciences to G.S.W., an Irish Research Council Consolidator Laureate Award to E.C.T., a UKRI Future Leaders Fellowship (MR/T021985/1) to S.C.V. and a Discovery Grant from the Natural Sciences and Engineering Research Council (NSERC) of Canada to P.A.F. S.C.V. and P.D. were supported by a Max Planck Research Group awarded to S.C.V. by the Max Planck Gesellschaft, and S.C.V. and E.Z.L. were supported by a Human Frontiers Science Program Grant (RGP0058/2016) awarded to S.C.V. L.J.G. was supported by an NSERC PGS-D scholarship.Exceptionally long-lived species, including many bats, rarely show overt signs of aging, making it difficult to determine why species differ in lifespan. Here, we use DNA methylation (DNAm) profiles from 712 known-age bats, representing 26 species, to identify epigenetic changes associated with age and longevity. We demonstrate that DNAm accurately predicts chronological age. Across species, longevity is negatively associated with the rate of DNAm change at age-associated sites. Furthermore, analysis of several bat genomes reveals that hypermethylated age- and longevity-associated sites are disproportionately located in promoter regions of key transcription factors (TF) and enriched for histone and chromatin features associated with transcriptional regulation. Predicted TF binding site motifs and enrichment analyses indicate that age-related methylation change is influenced by developmental processes, while longevity-related DNAm change is associated with innate immunity or tumorigenesis genes, suggesting that bat longevity results from augmented immune response and cancer suppression.Publisher PDFPeer reviewe

Obeticholic acid for the treatment of non-alcoholic steatohepatitis: interim analysis from a multicentre, randomised, placebo-controlled phase 3 trial

Background Non-alcoholic steatohepatitis (NASH) is a common type of chronic liver disease that can lead to cirrhosis. Obeticholic acid, a farnesoid X receptor agonist, has been shown to improve the histological features of NASH. Here we report results from a planned interim analysis of an ongoing, phase 3 study of obeticholic acid for NASH. Methods In this multicentre, randomised, double-blind, placebo-controlled study, adult patients with definite NASH,non-alcoholic fatty liver disease (NAFLD) activity score of at least 4, and fibrosis stages F2–F3, or F1 with at least oneaccompanying comorbidity, were randomly assigned using an interactive web response system in a 1:1:1 ratio to receive oral placebo, obeticholic acid 10 mg, or obeticholic acid 25 mg daily. Patients were excluded if cirrhosis, other chronic liver disease, elevated alcohol consumption, or confounding conditions were present. The primary endpointsfor the month-18 interim analysis were fibrosis improvement (≥1 stage) with no worsening of NASH, or NASH resolution with no worsening of fibrosis, with the study considered successful if either primary endpoint was met. Primary analyses were done by intention to treat, in patients with fibrosis stage F2–F3 who received at least one dose of treatment and reached, or would have reached, the month 18 visit by the prespecified interim analysis cutoff date. The study also evaluated other histological and biochemical markers of NASH and fibrosis, and safety. This study is ongoing, and registered with ClinicalTrials.gov, NCT02548351, and EudraCT, 20150-025601-6. Findings Between Dec 9, 2015, and Oct 26, 2018, 1968 patients with stage F1–F3 fibrosis were enrolled and received at least one dose of study treatment; 931 patients with stage F2–F3 fibrosis were included in the primary analysis (311 in the placebo group, 312 in the obeticholic acid 10 mg group, and 308 in the obeticholic acid 25 mg group). The fibrosis improvement endpoint was achieved by 37 (12%) patients in the placebo group, 55 (18%) in the obeticholic acid 10 mg group (p=0·045), and 71 (23%) in the obeticholic acid 25 mg group (p=0·0002). The NASH resolution endpoint was not met (25 [8%] patients in the placebo group, 35 [11%] in the obeticholic acid 10 mg group [p=0·18], and 36 [12%] in the obeticholic acid 25 mg group [p=0·13]). In the safety population (1968 patients with fibrosis stages F1–F3), the most common adverse event was pruritus (123 [19%] in the placebo group, 183 [28%] in the obeticholic acid 10 mg group, and 336 [51%] in the obeticholic acid 25 mg group); incidence was generally mild to moderate in severity. The overall safety profile was similar to that in previous studies, and incidence of serious adverse events was similar across treatment groups (75 [11%] patients in the placebo group, 72 [11%] in the obeticholic acid 10 mg group, and 93 [14%] in the obeticholic acid 25 mg group). Interpretation Obeticholic acid 25 mg significantly improved fibrosis and key components of NASH disease activity among patients with NASH. The results from this planned interim analysis show clinically significant histological improvement that is reasonably likely to predict clinical benefit. This study is ongoing to assess clinical outcomes